This Center project focuses on the issue as to whether patterns of gene expression are differentially changed in depressed versus control brain tissue and whether this information can be used to define dysregulations of circuitry which involve the dorsolateral prefrontal cortex (DLPFC), the anterior cingulate gyrus and the mediodorsal (MD) thalamic nuclei. The hypothesis to be explored is that there is a disruption in the associative circuitry involving these structures is neurodevelopmentally based and more sensitive to epigenetic stresses that are documented to precede the initial onset of depression. A body of emerging data shows that a subgroup of depressed patients have increased ventricular size, hypofrontality plus other neuropathological findings similar to those that led to the neurodevelopmental hypothesis of schizophrenia. Missing is direct neuropathological evidence such as that found in schizophrenia. We reported that three neuronal markers of the embryonic cortical subplate quantified in postmortem tissue from schizophrenic brains are abnormally distributed relative to matched normal controls and our recent data implicates the thalamus as well. The cortical subplates, formed during the second most direct data for a neurodevelopmental hypothesis of schizophrenia can be interpreted as a defect of neuronal migration or of programmed cell death in the subplate. A positive neuropathological finding could represent an important first step would support a neurodevelopmental hypothesis of depression and will point to a potentially productive focus on specific brain regions and molecules to be investigated in association with microarray analyses. A unique group of brains from depressed and control subjects have been collected, evaluated clinically by history, matched for age, gender and autolysis time and prepared for analysis by a novel method recently developed. Specific research aims include 1) Quantify and assess the morphology of interstitial neurons of the white matter stained for NADPH-d, microtuble associated protein 2 or anterior cingulate gyrus and MD thalamic nuclei; 3) Collect, characterize and match additional brains from depressed patients and controls; 4) Following initial microarray analysis, conduct in situ hybridization studies to identify sites of expression of differentially altered mRNAs.